Two novel neuropeptides in the brain, orexin-A and orexin-B were found lately as intrinsic ligands (Japanese Laid-open Patent Publication No. 10-229887; Cell, Vol. 92, 573-585, 1998) of G-protein coupled receptors, that is, orexin receptors mainly existing in the brain (WO 96/34877, Japanese Laid-open Patent Publication Nos. 10-327888, 10-327889 and 11-178588, etc.), and their biological functions draw attention.
It is also known that there are two subtypes in orexin receptors, namely, OX1 receptor (OX1R) as type-1 subtype and OX2 receptor (OX2R) as type-2 subtype.
At first, it is presumed for the reasons of the following (1) to (3) that orexins have something to do with control of feeding behavior. Namely, (1) the mRNA of prepro-orexin as the common precursor of orexin A and orexin B, and orexin immune reaction localize in the lateral hypothalamic region known as the feeding center from long ago (Handbook of the Hypothalamus, Vol. 2; Phisiology of the Hypothalamus, 557-620, 1980), (2) in rats fasted for 48 hours, the amount of prepro-orexin mRNA in the hypothalamus increases about 2.5 times compared with that under no fast, and (3) when a catheter is made to indwell in the lateral ventricle of a rat and orexin A or orexin B is administered, the amount of the food intake increases.
From experiments made using various animals, it is presumed that orexins participate not only in feeding behavior but also in various physiological actions such as emotional behavior, metabolism control, blood pressure control, hormone secretion control, body temperature control, sleep and awakening, secretion of stomach acids, control of the pain sensation (Idenshi Igaku, Vol.2, No.4, 618-620, 1998; Journal of Neuroscience, Vol.18, No.19, 7362-7971, 1998; Journal of Neuroscience, Vol.18, No.23, 9996-10015, 1998; Journal of Neuroscience, Vol.18, No.23, 9996-10015, 1998; Journal of Neuroscience, Vol.19, No.3, 1072-1087, 1999; Biochemical and Biophysical Research Communications, Vol.254, No.3, 623-627, 1999; Journal of Neuroscience, Vol.19,No.8, 3171-3182, 1999).
Lately, it was reported, based on experiments using dogs genetically falling in narcolepsy (Cell, Vol.98, 365-376, 1999) and experiments using mice lacking orexin (Cell, Vol.98, 437-451, 1999), that OX2 receptor, one of the two subtypes of orexin receptors, participates in narcolepsy.
Further, there is a report that in 7 patients among 9 patients of human narcolepsy, orexins in the cerebrospinal fluid, detectable in healthy individual, are lowered up to less than the detection limit (Lancet, Vol.355, 39-40, 2000), which suggests that also in humans, orexins have something to do with narcolepsy.
These various physiological actions in which orexins are presumed to participate are thought to be expressed via one or both of OX1 receptor and OX2 receptor as the two subtypes of orexin receptors.
As to compounds showing an antagonistic action on one or both of the two subtypes (OX1 receptor and OX2 receptor) of orexin receptors, one report has so far been made (WO 99/09024), but compounds disclosed in WO 99/09024 have phenylurea structure utterly different from tetrahydroisoquinoline structure which the compounds of the present invention have, and, moreover, in the WO, only antagonistic action on the OX1 receptor (HFGAN72 receptor) is shown, and antagonistic action on the OX2 receptor is not shown at all.
As compounds analogous in structure to the compounds of the invention, compounds represented by the following structural formula [II]: are disclosed in WO 99/23078 (hereinafter abbreviated as Document A). The compounds represented by the structural formula [II] in Document A have a tetrahydroisoquinoline ring bearing methoxy groups at the 6- and 7-positions as in the compounds of the invention, but do not have a branch at the α-position of the carbonyl group at the 2-position, and, in addition, are clearly different from the compounds of the invention in the side chain structure. Moreover, the compounds disclosed in Document A are described as endothelin antagonists, and in action, Document A has nothing to do with the present invention. Further, compounds represented by the following structural formula [III]: are disclosed in Japanese Laid-open Patent Publication (Tokuhyo-hei) No. 6-506440 (hereinafter abbreviated as Document B) as intermediates of the invention compounds described in Document B. The compounds represented by the structural formula [III] in Document B have a tetrahydroisoquinoline ring bearing methoxy groups at the 6- and 7-positions, but do not have a branch at the α-position of the carbonyl group at the 2-position, as in the compounds described in Document A, and are clearly different from the compounds of the present invention.